A new ligand for the urotensin II receptor

The cyclic peptide human urotensin II (U-II) has been recently recognized as the endogenous ligand of an orphan GPCR, subsequently named the UT receptor. No synthetic ligands are available for investigating this novel peptide-receptor system. A novel UT receptor ligand, [Orn(8)]U-II, was synthesized and evaluated in calcium functional assays performed on HEK293 cells expressing the recombinant rat and human UT receptor and in the rat aorta bioassay. [Orn(8)]U-II behaves as a full agonist (pEC(50) approximately equal 8) at both human and rat UT receptors in the FlipR calcium assay eliciting similar maximal effects as the natural ligand U-II. On the contrary, in the rat aorta bioassay, [Orn(8)]U-II behaves as a competitive and selective antagonist (pA(2)=6.56) showing however a small but consistent residual agonist activity. It is therefore proposed that [Orn(8)]U-II is a partial agonist at UT receptors.